An ill-behaved brain protein that escaped notice for over 90 years has unexpectedly emerged as a major possible cause of Alzheimer's disease. The unidentified protein forms a previously unknown variety of Alzheimer's lesion that appears to be just as widespread as the well-known senile plaques and neurofibrillary tangles. The finding, reported in the July issue of the American Journal of Pathology, could lead to new ways of diagnosing and treating the dreaded memory-depleting disease, which strikes 5% of people over age 65.

The brains of Alzheimer's patients had been known to harbor at least two microscopic defects ever since German neurologist Alois Alzheimer first described them in 1907. The senile plaques are composed mainly of a protein called amyloid, and the neurofibrillary tangles are made from one called tau that congeals in masses of paired helical filaments.

To study how the tau protein goes awry, Marie Luise Schmidt, working in the lab of University of Pennsylvania School of Medicine neurobiologists John Trojanowski and Virginia Lee, created a set of antibodies designed to bind to different sections of tau molecules. But several of the antibodies, especially one called AMY 117, didn't work quite as expected: They didn't bind to tau at all, but sought out plaques instead.

The researchers' hunch was that the tau antigens used to generate the antibodies were contaminated with proteins from the senile plaques. But when Schmidt stained autopsied brain sections using both AMY 117 and an antibody to amyloid, she was astonished to find that the two antibody types gravitated to two different sets of plaques--one of which had never before been glimpsed, apparently because it resists the traditional staining techniques. "Their existence couldn't have been suspected without these new antibodies," says Trojanowski. The team found AMY-binding plaques in all 32 Alzheimer's brains they examined; the plaques usually were near to, but not overlapping with, the senile plaques.

The discovery means that Alzheimer's researchers now have an entirely new set of pathological mechanisms to explore--and new challenges to overcome. "It could be that if you sweep away senile plaques and tangles and still have these AMY plaques, you would only be getting rid of two-thirds of the symptoms," says Trojanowski, who is currently purifying the AMY-binding protein with the goal of locating and cloning its gene. "This opens new vistas for us," agrees neuroscientist Zaven Khachaturian, director of the Alzheimer's Association's Ronald and Nancy Reagan Research Institute in Chicago. "It may give us new diagnostic tools, new insights about the causes of the disease, and new targets for treatment."